Methods such as solvent extraction and precipitation are currently employed to purify various types of polymers, such as those biodegradable polyesters used in controlled release formulations for implantation within body tissue. Dissolution of a sample of a polyester in a solvent and precipitation of certain fractions with a miscible non-solvent has been used to prepare materials with advantageous properties. For example, it has been found that certain methods of purification including selective solvent precipitation can provide biodegradable polyesters wherein the “initial burst effect”, an excessively high initial rate of release of a medicinal compound incorporated into the polyester upon implantation into body tissues, is reduced relative to that observed using the unpurified polyester.
For example, U.S. Pat. No. 4,728,721 discusses the presence of water-soluble unreacted monomers and water-soluble low molecular weight oligomers within the copolymers that are used to form microcapsules into which bioactive agents are incorporated. According to the inventors therein, the presence of these impurities tends to increase the initial burst effect. The patent provides methods for removal of some of these impurities by washing of a solid form of the polyester with water, or by dissolving the polyester in a water-soluble organic solvent and adding the solution to water.
U.S. Pat. No. 5,585,460 discusses the processing of polyesters used for the preparation of microcapsules, wherein polyesters are dissolved in a water-soluble organic solvent and precipitated in water to provide polyesters that are stated to have components with molecular weights under 1,000 (1 kDa) of less than about 3%.
U.S. Pat. No. 4,810,775 describes a process for purifying partly crystalline or amorphous polyesters wherein high shear forces are applied at the time of contacting the polyester with a precipitating agent such as water so that minute particles of the polyester are obtained. This patent describes that such treatment results in the removal of residual monomers and catalysts from the polyester.
U.S. Pat. No. 7,019,106 discusses a process for producing a lactic acid polyester of 15,000 to 50,000 in weight-average molecular weight, the content of polyesteric materials having not more than about 5,000 in weight-average molecular weight therein being not more than about 5% by weight. The process is characterized by hydrolysis of a high molecular weight lactic acid polyester and precipitation of the hydrolyzed product, which is stated to provide for a reduced burst effect.
U.S. patent application Ser. No. 60/901,435, filed Feb. 15, 2007 by the inventors herein, discusses a solvent precipitation process for producing a poly(lactide glycolide) polyester fraction (“PLGp”) that is advantageous in terms of reducing the initial burst effect.
A drawback of solvent extraction or precipitation processes is that they typically require relatively large amounts of organic solvents that are hazardous, difficult to handle, or difficult to dispose of. The typical organic solvents, which include methylene chloride and chloroform, are hazardous to humans (i.e., they are toxic or carcinogenic) and are hazardous to the environment. Considering the industrial scale on which the extraction processes would need to be performed in order to provide industrial quantities (e.g., kilograms or tons) of polymers, large quantities of organic solvents would be required. The high cost of disposing the organic solvents is an additional disadvantage of the current extraction procedures.
Supercritical fluid extraction refers to an extraction wherein a fluid at a temperature and pressure above its critical point is employed; or a fluid above its critical temperature, regardless of pressure, is employed. Below the critical point, the fluid can coexist in both gas and liquid phases, but above the critical point there is only one phase. Equipment, techniques, procedures, solvents and conditions (e.g., time, temperature and pressure) for carrying out supercritical fluid extraction are known to those skilled in the art. See, e.g., Supercritical Fluid Science and Technology, ACS Symposium Series: 406, K. P. Johnston, et al., editor, American Chemical Society, (1989), pp. 1-550; Supercritical Fluid Extraction-Principals and Practice, Second Edition, M. A. McHugh, et al., editors, Butterworth-Heinemann, (1994), pp. 1-512; Johnston, K. P. et al., “Supercritical Fluid Science and Technology”, ACS Symposium Series 406, American Chemical Society, (1989), 1-550; McHugh, Mark J., Supercritical Fluid Science and Technology, ACS Symposium Series: 406, K. P. Johnston, et al., editor, American Chemical Society, (1989), pp. 1-550; McHugh, M., et al., Supercritical Fluid Extraction-Principles and Practice, Second Edition, M. A. McHugh, et al., editors, Butterworth-Heinemann, (1994), pp. 1-512; McHugh, M., et al., Supercritical Fluid Extraction, 2nd Edition, (1994); Taylor, L. T., “Properties of Supercritical Fluids”, Supercritical Fluid Extraction. Chapter 2, John Wiley & Sons, New York, (1996), pp. 7-27; and Vilegas, J. H., et al., “Extraction of Low-polarity Compounds with Emphasis on Coumarin and Kaurenoic Acid from Mikania glomerata (Guaco) Leaves”, Phytochem. Anal., 8, Abstract Obtained from CAPLUS, Document No. 127:316461, (1997), pp. 266-270.
Suitable solvents useful in supercritical fluid extraction are disclosed, e.g., Supercritical Fluid Science and Technology, ACS Symposium Series: 406, K. P. Johnston, et al., editor, American Chemical Society, (1989), pp. 1-550; Supercritical Fluid Extraction-Principals and Practice, Second Edition, M. A. McHugh, et al., editors, Butterworth-Heinemann, (1994), pp. 1-512; Johnston, K. P. et al., “Supercritical Fluid Science and Technology”, ACS Symposium Series 406, American Chemical Society, (1989), 1-550; McHugh, Mark J., Supercritical Fluid Science and Technology, ACS Symposium Series: 406, K. P. Johnston, et al., editor, American Chemical Society, (1989), pp. 1-550; McHugh, M., et al., Supercritical Fluid Extraction-Principles and Practice, Second Edition, M. A. McHugh, et al., editors, Butterworth-Heinemann, (1994), pp. 1-512; McHugh, M., et al., Supercritical Fluid Extraction, 2nd Edition, (1994); Taylor, L. T., “Properties of Supercritical Fluids”, Supercritical Fluid Extraction. Chapter 2, John Wiley & Sons, New York, (1996), pp. 7-27; and Vilegas, J. H., et al., “Extraction of Low-polarity Compounds with Emphasis on Coumarin and Kaurenoic Acid from Mikania glomerata (Guaco) Leaves”, Phytochem. Anal., 8, Abstract Obtained from CAPLUS, Document No. 127:316461, (1997), pp. 266-270. One such supercritical fluid, not available for use as a solvent under conditions of standard temperature and pressure, is carbon dioxide. Carbon dioxide is a naturally occurring component of the atmosphere, produced by living organisms, and while there may be concern about excessive levels in the atmosphere in relation to global warming, in no way is carbon dioxide generally considered to be toxic or environmentally damaging in the way that, for example, chloroform is. Therefore, there is a need for industrial processes that can substitute the relatively non-toxic carbon dioxide as an extraction solvent for the more toxic halocarbons and the like in purification processes for polymer such as biodegradable polyesters that provide a product with desirable properties.